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Inhibition of Filovirus Replication by the Zinc Finger Antiviral Protein

Stefanie Müller,^1, Peggy Möller,^2, Matthew J. Bick,^1, Stephanie Wurr,¹ Stephan Becker,^2, Stephan Günther,¹ and Beate M. Kümmerer^1*

Department of Virology, Bernhard-Nocht-Institute for Tropical Medicine, 20359 Hamburg, Germany,¹ Institute of Virology, Philipps University Marburg, 35043 Marburg, Germany²

Received 26 July 2006/ Accepted 7 December 2006

The zinc finger antiviral protein (ZAP) was recently shown to inhibit Moloney murine leukemia virus and Sindbis virus replication. We tested whether ZAP also acts against Ebola virus (EBOV) and Marburg virus (MARV). Antiviral effects were observed after infection of cells expressing the N-terminal part of ZAP fused to the product of the zeocin resistance gene (NZAP-Zeo) as well as after infection of cells inducibly expressing full-length ZAP. EBOV was inhibited by up to 4 log units, whereas MARV was inhibited between 1 to 2 log units. The activity of ZAP was dependent on the integrity of the second and fourth zinc finger motif, as tested with cell lines expressing NZAP-Zeo mutants. Heterologous expression of EBOV- and MARV-specific sequences fused to a reporter gene suggest that ZAP specifically targets L gene sequences. The activity of NZAP-Zeo in this assay was also dependent on the integrity of the second and fourth zinc finger motif. Time-course experiments with infectious EBOV showed that ZAP reduces the level of L mRNA before the level of genomic or antigenomic RNA is affected. Transient expression of ZAP decreased the activity of an EBOV replicon system by up to 95%. This inhibitory effect could be partially compensated for by overexpression of L protein. In conclusion, the data demonstrate that ZAP exhibits antiviral activity against filoviruses, presumably by decreasing the level of viral mRNA.

Published ahead of print on 20 December 2006.

S. Müller and P. Möller contributed equally to this paper.

Present address: The Rockefeller University, 1230 York Avenue, New York, NY 10021.

Present address: Robert Koch-Institute, Nordufer 20, 13353 Berlin, Germany.

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